Patients with progressive metastatic papillary thyroid cancer (PTC) have a poor prognosis. Despite advances in developing new therapies complete responses have been elusive and non-durable responses are the best reported outcomes. The presence of gross local invasion and distant metastases are two predictors of death from PTC. We have focused on defining key regulators of these features in an effort to identify novel targets to improve treatment. We identified that the p21 activated kinase (PAK) signaling is activated in the invasive fronts of aggressive PTCs and determined that it regulated human thyroid cancer cell motility and proliferation in vitro. Because of the association between BRAF activation and tumor aggressiveness we analyzed the relationship between these two signaling molecules. We demonstrated that PAK activity was highly regulated by BRAF and that BRAF knock down inhibited PAK activity. Moreover, this effect was independent of MEK. We subsequently identified that PAK physically interacts with BRAF both overexpression and endogenous systems and that the complex occurs in mitosis consistent with a role in regulation cell division and growth. We have shown in vivo that acute activation of BRAF V600E in the thyroid is associated with increased levels of phosphorylated PAK. Finally, we have identified acquired mutations in upstream regulators of PAK in tumor samples from patients who developed resistance to BRAF inhibition. These data point to PAK being a critical downstream target of BRAF which plays an important functional role in PTC progression for tumors with RAS/RAF/ERK pathway activation. The hypotheses of this project is that PAK is a critical signaling node downstream of BRAF involved in thyroid cancer tumorigenesis and progression in vivo; that the mechanism of the interaction can be elucidated, and that it can be exploited to develop improved primary and secondary therapies for patients with progressive thyroid cancer and other patients with BRAF-mutated tumors.